Progestin therapy for maintaining amenorrhea

ABSTRACT

The present invention teaches that daily, cyclical vaginal delivery of progestin may be used to provide regular, predictable withdrawal bleeding during hormone replacement therapy. The present invention also teaches that constant administration of progestin in a water-insoluble, water-swellable cross-linked polycarboxylic acid polymer may be used to maintain amenorrhea. Either regimen is accompanied by a significant decrease in adverse side effects.

FIELD OF THE INVENTION

[0001] This invention relates to a method of administering progestintherapy in a manner that promotes controlled bleeding, rather than theirregular and unpredictable bleeding that normally accompanies progestinadministration.

BACKGROUND OF THE INVENTION

[0002] Progesterone is a naturally occurring steroid which is the mainsteroid secreted by women during their reproductive years. This steroidhas been studied extensively and has been found to be a major precursorin the biosynthesis of most other steroids, particularlyglucocorticoids, androgens and estrogens. Progesterone also stimulatesthe growth of the uterus and a number of specific changes in theendometrium and myometrium. It is essential for the development ofdecidual tissue and the differentiation of luminal and glandularepithelial tissue. Progesterone also plays several roles in gestation,including breast enlargement, inhibition of uterine contractility,maintenance of gestation, immunological protection of the embryo, andinhibition of prostaglandin synthesis.

[0003] Progestins include the natural progestin, progesterone, as wellas the synthetic progestins, such as medroxyprogesterone acetate (MPA).Progestins have been used pharmaceutically in the treatment of a numberof clinical disorders such as luteal phase deficiency, dysfunctionaluterine bleeding, endometriosis, endometrial carcinoma, benign breastdisease, pre-eclampsia, and assisting in vitro fertilization, preventingearly abortion and reducing the occurrence of endometrial hyperplasia inestrogen replacement therapy (ERT).

[0004] The most common progestational agents used are the syntheticprogestins, which are accompanied by undesirable side effects such asdepression and water retention. Additionally, many of the syntheticprogestins derived from 19-nor-testosterone reverse the positive effectsof estrogen on lipoprotein (HDL) levels. In contrast, naturalprogesterone does not cause water retention, is rarely associated withdepression and has no adverse effects upon lipid levels.

[0005] There have been many difficulties in administering naturalprogesterone at the appropriate serum and tissue levels to patients.When given orally, progesterone is rapidly metabolized. See e.g.,Adlecruz, H. and Martin, F. J. Steroid Biochem., 13:231-244 (1980) andMaxson, W. S., and Hargrove, J. T., Fertil. Steril., 44:622-626 (1985).

[0006] Rectal administration of progestins has also been attempted with25 mg and 100 mg doses of natural progesterone, which achieved peakplasma levels at 4 to 8 hours after administration followed by a gradualdecline, but the maintenance of a stable plasma level has been difficultwith this route. Maxson, W. S. Clinical Obstet. Gynecol., 30: 465-477(1987); Nillius, S. J. and Johansson, E. D. B. Am. J. Obstet. Gynecol.,110: 470-479 (1971). Sublingual administration resulted in rapidappearance of progesterone in the serum reaching peak values of up to 10times basal levels, but returning to basal levels within twenty-fourhours. Villanueva, B., et al., Fertil. Steril., 35: 433-437 (1981).Nasal administration, using 20 mg and 30 mg doses, achieved mean maximumconcentrations of 2.1 and 4.1 ng/ml, respectively, at approximately 30and 240 minutes, respectively.

[0007] Intramuscular administration of progesterone has been attemptedwith 100 mg doses which achieved 40 to 50 ng/ml serum concentrations intwo to eight hours. Nillius, S. J. and Johansson, E. D. B., Am. J.Obstet. Gynecol., 110: 470-479 (1971). Such administration has shownthat such injections need to be given every day or on alternate days toproduce results. Whitehead, M., and Godfree, V. in Hornone ReplacementTherapy, Churchill Livingston Edinburgh 1992, pp 91. Subdermaladministration has also been assayed, with six 100 mg progesteronepellets being implanted in post-partum women. Croxatto, H. B., et al.,Acta Endocrinol, 100: 630 (1982). Progesterone levels reached a peak of4.4 ng/ml within the first week after insertion and reached a mean peaklevel of 1.9 ng/ml six months after implantation. Progestin implants arenot practical in cyclical therapy and moreover, physiological levels ofprogestin are not achieved. (“Cyclical” therapy means that the progestinis administered off and on, typically for a portion of each 28-day cycleor each calendar month. For example, cyclical administration could bedaily, or every other day, only on days 15 through 20 of each 28-daycycle, or only for the first five days each month. “Constant” or“continuous” therapy means that the drug is administered regularly,whether it is daily, every other day, weekly, or otherwise, withoutregard, for example, to the 28-day cycle or the calendar month.)

[0008] It has been demonstrated that topically applied radioactiveprogesterone can be absorbed through the skin. Mauvais-Jarvis,Progesterone., et al., J. Clin. Endocrinol. Metab., 29: 1580-1587(1969). Labeled metabolites were recovered in the urine at 48 hoursafter topical administration. However, the absorption was only 10% ofthe applied dose. The high fat solubility of progesterone is responsiblefor the prolonged retention of this steroid and the extensive localmetabolism reduces the systemic effect of the steroid. It has been shownthat treatment with topical application of progesterone to the breastproduces no significant endometrial effects. Sitruk-Ware, R., et al., J.Clin. Endocrin. Metab., 44: 771-774 (1977).

[0009] Progestins have also been administered vaginally topostmenopausal women receiving ERT. 50 mg/ml of progesterone in asuspension containing carboxymethyl cellulose and methyl cellulose whichwas inserted into the vagina was characterized by a rapid absorption ofthe progesterone across the vaginal mucosa. There was an immediateappearance of the hormone in the peripheral circulation resulting in a10-fold increase over the baseline serum levels (0.34 ng/ml) after 15minutes. The peak levels were obtained 1 or 2 hours after administrationand represented a thirty- to forty-fold increase over baseline levels(12.25 ng/ml). The serum levels remained at this level over the nextseven hours, declining over the next ten hours to 3.68 ng/ml.Villanueva, B., et al., Fertil. Steril., 35: 433-437 (1981). Theseresults suggested that the absorption of progestins was enhanced inwomen also undergoing ERT.

[0010] As described in U.S. Pat. No. 5,543,150 (“the ′150 Patent”),which is incorporated herein by reference, it now appears that thebioadhesive formulation used with the instant invention can providelocal vaginal administration of progestins to yield significant localdrug levels while maintaining serum levels low enough to avoid most ofthe undesired side effects. See also, Warren, M. P., et al., Evaluationof Crinone®, a Transvaginally Administered Progesterone ContainingBioadhesive Gel, in Women with Secondary Amenorrhea, Abstract, Presentedat the 8th International Congress on the Menopause, Sydney, Australia,1996. And as described in U.S. patent application Ser. No. 08/743,153,which is incorporated herein by reference, it also appears thatprogesterone can be administered for the purpose of treating or reducingischemia or incidence of cardiovascular events.

[0011] Treatments of menopausal and post-menopausal women involvingadministration of progestins in cyclical association with estrogeninduces the physiological sequence of endometrial changes normallyencountered in the menstrual cycle. Such treatments usually administerprogestins, usually daily, over a period of about 10 to 14 days eachmonth. However, the withdrawal bleeding that results from suchadministration is typically irregular and unpredictable, and oftenbegins as early as about the fourth day following the first progestindose. See, Archer, D. F., et al., Bleeding Patterns in Post-menopausalWomen Taking Continuous Combined or Sequential Regimens of ConjugatedEstrogens with Medroxyprogesterone Acetate, Obstet. Gynecol., 83:686-92(1994).

SUMMARY OF THE INVENTION

[0012] The present invention comprises a method of cyclical vaginaladministration of progestins daily, while avoiding significant adverseside effects, in order to avoid the often-erratic monthly withdrawalbleeding normally associated with cyclical progestin treatment, andinstead to provide regular withdrawal bleeding upon completion of theprogestin-administration period. Thus the invention provides thebenefits of cyclical progestin therapy without the inconvenience andcomplications of irregular withdrawal bleeding, and without common sideeffects.

[0013] The present invention also comprises a method of constant vaginaladministration to maintain complete amenorrhea while avoidingsignificant adverse side effects. Thus, the invention provides completeamenorrhea without the periodic breakthrough bleeding or spotting oftenobserved with other methods for three to six months, and withoutsignificant adverse side effects often resulting from other methods.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014]FIG. 1 illustrates the bleeding pattern produced by a 45 mg. doseof progestin (CRINONE® 4% progesterone gel) cyclically administeredevery day vaginally.

[0015]FIG. 2 illustrates the bleeding pattern produced by a 45 mg . doseof progestin (CRINONE® 4% progesterone gel) cyclically administeredevery other day vaginally, as reported in Warren, M. P., et al.,Evaluation of Crinone®, a Transvaginally Administered ProgesteroneContaining Bioadhesive Gel, in Women with Secondary Amenorrhea,Abstract, Presented at the 8th International Congress on the Menopause,Sydney, Australia, 1996.

[0016]FIG. 3 illustrates the bleeding pattern produced by a 90 mg. doseof progestin (CRINONE® 8% progesterone gel) cyclically administeredevery other day vaginally, also as reported in Warren, M. P., et al.,Evaluation of Crinone® . . . , cited above.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention is related to a method of treating withprogestins comprising use of a therapeutically effective amount ofprogestin for vaginal administration to menopausal and post-menopausalwomen in an improved regimen in order to promote regular withdrawalbleeding. Daily vaginal dosing of CRINONE® 4% progesterone gel toestrogenized women was demonstrated to produce endometrialtransformation, but with monthly withdrawal bleeding consistently andpredictably occurring only after the progestin administration iscomplete—only upon true “withdrawal” from the progestin administered.

[0018] The present invention is also related to a method of treatingwith progestins comprising use of a therapeutically effective amount ofprogestin for vaginal administration to menopausal and post-menopausalwomen in an improved regimen for maintaining amenorrhea. Constant ratherthan cyclical association of estrogens and progestins is proposed inmenopausal and post-menopausal women in order to avoid monthlywithdrawal bleeding altogether. Azzawi, A. J., de Ziegler, D., VaginalProgesterone Gel-based Continuous Combined HRT as an AmenorrheicRegimen, Presented at IV European Congress on Menopause, Vienna, October1997. Constant, or regular, administration of progestins throughout themonth, without break, promotes amenorrhea, or a total lack of bleeding.However, just as with pregnancy-induced amenorrhea, constantadministration of progestins does not produce the often-desiredphysiological endometrial changes associated with the menstrual cycle,during which the endometrium undergoes monthly transformation andshedding. Instead, the endometrium undergoes a maintained state ofatrophy.

[0019] Even when endometrial atrophy, and thus amenorrhea, are desiredto be maintained, continuous daily vaginal administration of progestinsis impractical and inconvenient. We also have studied the sustainedrelease properties of the progestin gel described in the '150 Patent,and achieved constant uterine exposure to constant administration ofprogesterone while limiting vaginal applications to a reasonable twice aweek. CRINONE® 8% progesterone gel, available from Wyeth-AyerstLaboratories, of Philadelphia, Pa., was shown to maintain amenorrheaupon bi-weekly dosing to women already receiving constant transdermalestrogen therapy. This administration achieved and maintainedendometrial atrophy as expressed by the high incidence of amenorrhea andthin endometrium as revealed by ultrasound examination. This simple,easy regimen, devoid of the common side effects and problems encounteredwith synthetic progestins or oral administration, is a new clinicaloption for menopausal and post-menopausal women wishing to avoidwithdrawal bleeding altogether while receiving progestins. See,'Fanchin, R., de Ziegler, D., et al., Transvaginal Administration ofProgesterone: Dose-response Data Support a First Uterine Pass Effect,Obstet. Gynecol., 90:396-401 (1997).

[0020] Contrary to other administrations of progestin discussed in theart, the regimen of daily cyclical treatment with progestin producedreliable, regular withdrawal bleeding only after the progestinadministration period. This provides substantial convenience to women onprogestin therapy, without the uncertainty and inconvenience ofirregular and unpredictable onset of bleeding. And the regimen ofconstant treatment with progestin maintained complete amenorrhea. Thisprovides convenience to women seeking amenorrhea, without the periodicbreakthrough bleeding or spotting common for three to six months withother methods of treatment.

[0021] The invention comprises use of a progestin formulation for dailyvaginal administration while promoting regular withdrawal bleeding aftermonthly progestin administration is completed, or for constant vaginaladministration while maintaining complete amenorrhea. Preferably, theprogestin formulation comprises progesterone and a bioadhesive carrier,which may be in a gel formulation, containing a polymer base designed togive controlled and prolonged release of the progesterone through thevaginal mucosa. This route of administration also avoids first-passmetabolism problems as well as many significant adverse events.

[0022] The present invention comprises a dosing regimen and manner oftreating with progestin in hormone replacement therapy. Preferably,about 45 mg to 90 mg of progesterone is administered at one time. Thecomposition for cyclical administration is preferably administered dailyfor part of each cycle, which preferably is based on calendar months forconvenience. The composition for constant administration is preferablyadministered about twice per week. Most preferably, only naturalprogesterone itself is used.

[0023] The specific drug delivery formulations preferred, which werechosen and used in Examples 1 and 2, CRINONE® 8% and 4 +L% progesteronegels from Wyeth-Ayerst Laboratories, Philadelphia, Pa., comprisecross-linked polycarboxylic acid polymer formulations, generallydescribed in U.S. Pat. No. 4,615,697 to Robinson (hereinafter “the '697patent”) and in the '150 Patent, each of which is incorporated herein byreference. In general, at least about eighty percent of the monomers ofthe polymer in such a formulation should contain at least one carboxylfunctionality. The cross-linking agent should be present at such anamount as to provide enough bioadhesion to allow the system to remainattached to the target epithelial surfaces for a sufficient time toallow the desired dosing to take place.

[0024] For vaginal administration, such as in the examples below,preferably the formulation remains attached to the epithelial surfacesfor a period of at least about twenty-four to forty-eight hours. Suchresults may be measured clinically over various periods of time. Thispreferred level of bioadhesion is usually attained when thecross-linking agent is present at about 0.1 to 6.0 weight percent of thepolymer, with about 1.0 to 2.0 weight percent being most preferred, aslong as the appropriate level of bioadhesion results. Bioadhesion canalso be measured by commercially available surface tensiometers utilizedto measure adhesive strength.

[0025] The polymer formulation can be adjusted to control the releaserate of the progesterone by varying the amount of cross-linking agent inthe polymer. Suitable cross-linking agents include divinyl glycol,divinylbenzene, N,N-diallylacrylamide, 3,4-dihydroxy-1,5-hexadiene,2,5-dimethyl-1,5-hexadiene and similar agents.

[0026] A preferred polymer for use in such a formulation isPolycarbophil, U.S.P., which is commercially available from B.F.Goodrich Speciality Polymers of Cleveland, Ohio under the trade nameNOVEON®-AA1. The United States Pharmacopeia, 1995 edition, United StatesPharmacopeial Convention, Inc., Rockville, Md., at pages 1240-41,indicates that polycarbophil is a polyacrylic acid, cross-linked withdivinyl glycol.

[0027] Other useful bioadhesive polymers that may be used in such a drugdelivery system formulation are mentioned in the '697 patent. Forexample, these include polyacrylic acid polymers cross-linked with, forexample, 3,4-dihydroxy-1,5-hexadiene, and polymethacrylic acid polymerscross-linked with, for example, divinyl benzene.

[0028] Typically, these polymers would not be used in their salt form,because this would decrease their bioadhesive capability. Suchbioadhesive polymers may be prepared by conventional free radicalpolymerization techniques utilizing initiators such as benzoyl peroxide,azobisisobutyronitrile, and the like. Exemplary preparations of usefulbioadhesives are provided in the '697 patent.

[0029] The bioadhesive formulation may be in the form of a gel, cream,tablet, pill, capsule, suppository, film, or any other pharmaceuticallyacceptable form that adheres to the mucosa and does not wash awayeasily. Different formulations are further described in the '697 Patent,which is incorporated herein by reference.

[0030] Additionally, the additives taught in the '697 patent may bemixed in with the cross-linked polymer in the formulation for maximum ordesired efficacy of the delivery system or for the comfort of thepatient. Such additives include, for example, lubricants, plasticizingagents, preservatives, gel formers, tablet formers, pill formers,suppository formers, film formers, cream formers, disintegrating agents,coatings, binders, vehicles, coloring agents, taste and/or odorcontrolling agents, humectants, viscosity controlling agents,pH-adjusting agents, and similar agents.

[0031] A preferred progestin composition is CRINONE® 4% or 8%progesterone gel, which consists of the following ingredients discussedfurther in the '150 Patent: 4 or 8 weight percent progesterone, 12.9weight percent glycerin, 4.2 weight percent mineral oil, 2 weightpercent polycarbophil (available from B.F. Goodrich Specialty Polymersof Cleveland, Ohio), 1 weight percent hydrogenated palm oil glyceride, 1weight percent carbomer 934P (available from B.F. Goodrich), 0.08 weightpercent sorbic acid, 0 - 2 weight percent sodium hydroxide, and theremaining part purified water. (This is the same basic formula discussedin the '150 Patent at column 6, lines 44-52, except that methylparabenis not presently included.) Sorbic acid is a preservative, which may besubstituted by any other approved preservative, such as methylparaben,benzoic acid or propionic acid.

[0032] Carbomer 934P is a gel former, which may be substituted by othergel formers, such as carbomer 974P, carbomer 980, methyl cellulose orpropyl cellulose.

[0033] Glycerin is a humectant; alternative humectants include, forexample, propylene glycol or dipropylene glycol.

[0034] Mineral oil and hydrogenated palm oil glyceride are lubricatingagents; alternatives include, for example, any mineral or vegetable oil,such as canola oil, palm oil, or light mineral oil.

[0035] Sodium hydroxide is simply a strong base for purposes ofcontrolling the pH level; other bases commonly used for that purpose maybe substituted.

[0036] Preparation of the formulation involves hydration of thepolymers, separate mixing of water-soluble ingredients (the “polymerphase”) and oil-soluble ingredients (the “oil phase”), heating andmixing of the two phases, and homogenization of the mixture. Allingredients listed above are well-known and readily available fromsuppliers known in the industry.

[0037] The polymer phase may generally be prepared by mixing the water,sorbic acid, polycarbophil, and carbomer are added. The polymers arehydrated by mixing for several hours, generally about 2-3 hours until auniform, smooth, homogenous, lump-free gel-like polymer mixture isobtained. When the polymers are completely hydrated, the progesterone isadded and mixed in, until a homogeneous suspension is obtained.

[0038] The oil phase is generally prepared by melting together theglycerin and mineral oil, by heating to 75 to 78° C. The mixture iscooled to about 60° C., while the polymer phase is warmed to about thesame temperature. The polymer phase is then added to the heated oilphase. The two phases are mixed thoroughly, producing a uniform, creamywhite product. If needed, mix in sodium hydroxide to produce a pH ofabout 2.5-3.5, generally about 3. When the mixture has cooled, it isde-aerated. The resulting product is aseptic because of the nature ofthe preparation and pH as well as the presence of the preservative.

[0039] As will be apparent to those skilled in the art, the compositionof the formulation can be varied to affect certain properties of theformulation. For example, the concentration of the bioadhesive polymercan be adjusted to provide greater or lesser bioadhesion. The viscositycan be varied by varying the pH or by changing the concentration of thepolymer or gel former. The relative concentrations of the oils comparedto the water can be varied to modulate the release rate of the progestinfrom the drug delivery system. The pH can also be varied as appropriateor to affect the release rate or bioadhesiveness of the formulation.

[0040] The progestin formulation may be delivered vaginally in any of avariety of fashions known in the art, such as by plunger, douche,suppository, or manually. A preferred method of delivery is using adevice such as that described in U.S. Pat. No. Des. D345,211 or U.S.Pat. No. Des. D375,352, which disclosures are incorporated herein byreference. Such a device is an oblong hollow container, with one endcapable of being opened and the other end containing most of thecomposition to be delivered and capable of being squeezed. Such devicesallow for pre-measurement of the amounts of product to be delivered in asingle dosage by a sealed container which may be used relatively easily.The containers also maintain the product in an aseptic environment untiluse. Upon use the container is opened and the open end is inserted intothe vagina, while the other end is squeezed to expel the contents of thecontainer into the vagina. A ‘kit’ of the product can therefore containa single dose or multiple doses of the product.

EXAMPLE 1 Daily vs. Twice-Weekly Cyclical, and Constant, Administrationof Progesterone

[0041] This study was designed to examine the use of CRINONE®progesterone gel in menopause as part of hormone replacement therapy(“HRT”) in cyclical association with estrogen therapy, and in constantcombined association with estrogen for a no-bleed regimen. The resultsfrom the first groups of subjects in the study are reported here. (Thestudy continued with additional subjects; complete results from allsubjects, including those discussed in Example 1, are reported below atExample 3.)

[0042] Two groups of women were assembled, each with 20 women. Group Iranged in age from 38 to 55 years old, and each woman exhibitedmenopausal symptoms or was already on HRT. Group II ranged in age from50 to 64, and each woman was more than 3 years into menopause(amenorrhea), or on HRT with cyclical bleeding. None of the woman ineither group exhibited abnormal bleeding or any other uterine pathology.

[0043] Group I received estrogen continuously (PREMARIN® (0.625 mg)conjugated estrogens (Wyeth-Ayerst Laboratories, Philadelphia, Pa.),PROGYNOVA® (2 mg) estradiol valerate (Schering A. G., Berlin, Germany),or ESTRADERM® TTS (50 mg) or ESTRADERM® MX 0.05 (0.050 mg) estrogenpatches (Novartis Pharmaceutical, Basel, Switzerland)), and CRINONE® 4%progesterone gel (45 mg. progesterone) every day in the morning fromcycle days 15 to 24. (For practical purposes and convenience,administration took place monthly on calendar days 1 to 10,corresponding to cycle days 15 to 24.) Group II received ESTRADERM® Mx(50 mg) estrogen patch (Novartis Pharmaceutical) twice weekly,continuously (or if intolerant to the patch, OESTROGEL® estrogen gel(Besins-Iscovesco Laboratories, Paris, France) every day), and CRINONE®8% progesterone gel (90 mg progesterone) twice a week in the morning,continuously.

[0044] For all subjects, the baseline clinical assessment included aclinical exam, and a vaginal ultrasound to screen for women on nopre-existing treatment less than 5 mm thick, and for women on HRT orwith persistent ovarian function less than 10 mm thick. In Group 1, thewomen were informed to report any vaginal bleeding other than withdrawalbleeding defined as menses-like bleeding starting after the last (tenth)progesterone dose.

[0045] Treatments were administered in months six to twelve, afterbaseline was established for months zero to six. At the conclusion, allwomen were again clinically examined, including a vaginal ultrasound,and endometrial sampling if the ultrasound showed for a group 1 woman anendometrium greater than 10 mm thick, or for a group 2 woman anendometrium greater than 5 mm thick. The results are reported in Charts1 and 2 and in FIG. 1. CHART 1 ULTRASOUND - ENDOMETRIAL THICKNESS (mm.,mean ± SEM) On treatment Baseline (6-12 months) Group I 4.5 ± 1.5  4.5 ±0.8 Group II No HRT 3.2 ± 0.6  No bleed 3.3 ± 1.0 HRT 6.3 ± 1.39Bleeding 3.5 ± 1.1

[0046] CHART 2 BLEEDING PATTERN Mean Age Type of bleeding n %Disposition Group I 46.8 ± 4.1 Expected Withdrawal only 19/20 95 100%Continued HRT Abnormal Breakthrough and/or  1/20  5 n = 1; discontinuedother abnormal HRT bleeding Group II 57.5 ± 4.6 Expected Amenorrhea15/20 75 n = 13 (87%) (no bleed) continued HRT n = 1: changed regimen n= 1: stopped HRT Acceptable Isolated spotting/  4/20 20 n = 4: all mildbleeding continued Unacceptable Heavy bleeding/  1/20  5 n = 1: D&Crepeated spotting Benign histology

[0047]FIG. 1 shows the proportion of patients with bleeding, and thetiting of that bleeding, for the Group 1 subjects being administereddaily progesterone. In contrast, FIGS. 2 and 3 show the proportion ofpatients with bleeding, and the timing of that bleeding, for patientsreceiving, respectively, 45 mg. and 90 mg. of progesterone (CRINONE® 4%or 8% progesterone gel) every other day, as reported by Warren, et al.,cited herein previously.

[0048] As detailed in Chart 2 and FIG. 1, cyclical administration toGroup 1 subjects of daily CRINONE® progesterone gel resulted in 95% ofthe subjects experiencing withdrawal bleeding only after the monthlyprogestin dosing periods. Thus daily dosing profoundly changed thebleeding pattern, resulting in regular bleeding within 1 to 4 days ofcompleting monthly progesterone treatment, with no other form ofbleeding in 95% of the patients. All of these regularly-bleedingpatients continued their HRT program, while the singleirregularly-bleeding patient discontinued HRT altogether.

[0049] In contrast, CRINONE® progesterone gel cyclically administeredevery other day produced bleeding patterns similar to those achievedwith synthetic progestins (MPA), regardless of the strength of theCRINONE® progesterone gel used (4% (45 mg) or 8% (90 mg)). See Warren,et al., cited previously herein regarding CRINONE® progesterone gel andreflected in FIGS. 2 and 3, in comparison with Archer, et al., citedpreviously herein regarding MPA. Such a daily regimen is thus veryattractive when perfect control of bleeding is desired.

[0050] For Group 2, with constant CRINONE® progesterone gel dosing, 75%of the subjects did not experience withdrawal bleeding, and only 5% (oneof the twenty subjects) experienced heavy bleeding or repeated spotting.Of the 15 patients without bleeding, 13 continued their HRT program (asdid all 4 of the patients with isolated spotting or mild bleeding), 1changed her regimen and 1 stopped HRT. The sole subject with heavybleeding or repeated spotting underwent a D&C (dilatation andcurettage), with benign histology; her HRT was discontinued.

[0051] Thus, CRINONE® progesterone gel administered twice a weekcontinuously in estrogenized menopausal woman maintained completeamenorrhea in a majority of patients. Pilot data elsewhere showedsimilar efficacy with CRINONE® 4% progesterone gel (45 mg.progesterone). The lack of side effects makes this regimen a veryattractive option for menopausal women who do not wish to have menses.Prior regimens have often led to periodic breakthrough bleeding orspotting for three to six months.

EXAMPLE 2

[0052] Constant Administration of Progesterone Eighteen women at leastthree years into menopause or at least 53 years of age receivedtransdermal estrogen therapy (ESTRADERM® TTS (50 mg) or ESTRADERM® Mx(50 mg) estrogen patches) constantly, and twice per week application of1.125 g of CRINONE® 8% progesterone gel (90 mg. progesterone). Anultrasound was performed at 6 months.

[0053] After 6 months of treatment, 13 of 18 subjects had remainedamenorrheic during treatment. Of the 5 women who experienced bleeding, 4had only mild and intermittent bleeding, and only 1 had heavierbleeding. At six months, all women had an endometrium less than 5 mmthick. Of the 13 amenorrheic women, 10 were satisfied and continuedtheir treatment, 2 switched to a different HRT regimen and 1 stopped HRTaltogether.

[0054] Again, CRINONE® progesterone gel administered continuously, twicea week, maintained complete amenorrhea in a majority of patients.

EXAMPLE 3 Daily vs. Twice-Weekly Cyclical, and Constant, Administrationof Progesterone

[0055] In a continuation of the study reported above in Example 1, thisstudy continued to examine the use of CRINONE® progesterone gel inmenopause as part of hormone replacement therapy (“HRT”) in cyclicalassociation with estrogen therapy, and in constant combined associationwith estrogen for a no-bleed regimen. Group I included a total of 69women, and Group II included a total of 67 women. Group II women weremore than three years into menopause, or more than 53 years of age, andfree of bleeding disorders.

[0056] Women in both groups were evaluated after six months oftreatment, and at six-month intervals thereafter. Endometrial thicknesswas evaluated on ultrasound, and the results through eighteen months oftreatment are reported at Chart 3. Bleeding patterns through six monthsare reported at Chart 4. In a subset of fourteen women evaluated ateighteen months, twelve remained amenorrheic for the entire observationperiod. CHART 3 ULTRASOUND - ENDOMETRIAL THICKNESS (mm., mean ± SEM) Ontreatment Baseline (6-18 months) Group I 4.1 ± 1.5  4.9 ± 0.9  Group IINo HRT 3.7 ± 0.7  No bleed 3.9 ± 1.2  HRT 6.7 ± 1.45 Bleeding 3.8 ± 1.76

[0057] CHART 4 BLEEDING PATTERN Mean Age Type of bleeding n % Group I 50± 1.5 Expected Withdrawal only 63/69 91.3 Abnormal Breakthrough  6/698.7 and/or other abnormal bleeding Group II 58 ± 5.3 Expected Amenorrhea54/67 80.6 (no bleed) Acceptable Isolated spotting/  9/67 13.4 mildbleeding Unacceptable Heavy bleeding/  4/67 6 repeated spotting

[0058] Consistent with Chart 2 and FIG. 1 discussed above in Example 1,Chart 4 demonstrates that administration to Group 1 subjects of dailyCRINONE ® progesterone gel resulted in 91.3% (sixty three out of sixtynine) of the subjects experiencing withdrawal bleeding only after eachof the six monthly progestin dosing periods. Thus daily dosingprofoundly changed the bleeding pattern, resulting in regular bleedingwithin 1 to 4 days of completing monthly progesterone treatment, with noother form of bleeding in 91.3% of the patients. Of these sixty threesubjects, fifty eight, or 92%, elected to remain on the vaginalprogesterone for HRT, two opted for another treatment option and threediscontinued all hormone treatment.

[0059] For Group 2 subjects, with constant CRINONE® progesterone geldosing, 80.6% of the subjects did not experience withdrawal bleeding,only 6% experienced heavy bleeding or repeated spotting, and 13.4%experienced isolated spotting or mild bleeding at anytime during thesix-month evaluation period.

[0060] Thus, results from the larger pool of test subjects (relative tothe first groups reported above at Example 1) further demonstrates thatprogestin administered twice a week continuously in estrogenizedmenopausal woman maintained complete amenorrhea in the vast majority oftest subjects. And the cyclical daily administration of progestin inwoman undergoing HRT provided much more reliable and regular withdrawalbleeding. Especially in combination with the lower incidence of sideeffects, either regimen should lead to improved HRT compliance.

[0061] Any and all publications, patents, and patent applicationsmentioned in this specification are indicative of the level of skill ofthose skilled in the art to which this patent pertains. Allpublications, patents, and patent applications are herein incorporatedby reference to the same extent as if each individual publication,patent, or patent application was specifically and individuallyindicated to be incorporated by reference.

[0062] Reasonable variations, such as those which would occur to askilled artisan, can be made without departing from the spirit and scopeof the invention.

We claim:
 1. A method of promoting regular withdrawal bleeding in awoman undergoing cyclical progestin administration comprising cyclicalvaginal delivery of progestin via a drug delivery system in an amountsufficient to cause secretory transformation of the endometrium whileavoiding significant adverse side effects.
 2. The method of claim 1wherein the drug delivery system comprises a water-insoluble,water-swellable cross-linked polycarboxylic acid polymer.
 3. The methodof claim 2 wherein the polymer is polycarbophil.
 4. The method of claim3 wherein the progestin is progesterone.
 5. The method of claim 4wherein the amount of progesterone delivered is about 45 mg to about 90mg per dose.
 6. The method of claim 4 wherein the drug delivery systemadditionally comprises at least one adjuvant.
 7. The method of either ofclaims 2 and 5 wherein the drug delivery system is administered dailyduring a set portion of every calendar month.
 8. The method of claim 3wherein the woman is also being treated with estrogen.
 9. The method ofclaim 7 wherein the woman is also being treated with estrogen.
 10. Amethod of maintaining amenorrhea in a woman undergoing constantprogestin administration comprising constant vaginal administration ofprogestin via a drug delivery system in an amount sufficient to causeendometrial atrophy while avoiding significant adverse side effects. 11.The method of claim 10 wherein the drug delivery system comprises awater-insoluble, water-swellable cross-linked polycarboxylic acidpolymer.
 12. The method of claim 11 wherein the polymer ispolycarbophil.
 13. The method of either of claims 10 and 12 wherein theprogestin is progesterone.
 14. The method of claim 10 wherein theprogestin is administered about twice per week.
 15. The method of claim13 wherein the progestin is administered about twice per week.